A number of antihypertensive medicines are the chemical entities containing N,N'-substituted piperazines having one nitrogen acylated and the other linked to cyclized Guanidines of the general Formula 1. ##STR3## Suitable substituents for R may be those listed below: ##STR4##
A number of antihypertensive medicines are the chemical entities of Formula 1 wherein the methoxy substituents are at the 6 and 7 positions as shown below in Formula 1A: ##STR5## where ##STR6## the medicine in Formula 1A is Doxazosin. where ##STR7## the medicine in Formula 1A is Terazosin. where ##STR8## the medicine in Formula 1A is Prazosin. where ##STR9## the medicine in Formula 1A is Tiodazosin.
The following compounds are thus presented: ##STR10##
The compounds of general Formula 1 have been prepared by a number of approaches. One of the important approaches is that (Scheme 1) a 4-amino-6,7-dialkoxy quinazoline, substituted at C-9 position with a good leaving group X, is condensed with N-Acylated piperazines (see for example U.S. Pat. Nos. 4,093,726, 4,112,097 and 4,188,390, EP 0 028 473 Oct. 16, 1980; J. Med Chem. 1987, 30, 49-57 and references therein). ##STR11##
Another approach (Scheme 2) involves the condensation of a urea derivative with N-Acylated piperazines and cyclization of the resultant urea derivatives with appropriate reagents to give the required products. ##STR12## See Canadian Patent Application No. 2,077,252.
Both of the above methods use an N-Acyl piperazine as one of the active components. The N-Acyl piperazines of general Formula 2 have been prepared by a number of methods which may be classified into one general method. They all involve coupling reactions between an activated acid derivative A and piperazine (Scheme 3). ##STR13## R may be selected from ##STR14## Y is ##STR15## or other activating groups.
These activated acid derivatives (A) are generally prepared from corresponding acids or normal esters such as methyl, ethyl or other lower alkyl esters. Most of the processes taught by patents use acid chlorides (Y.dbd.Cl, Scheme 3) as activated acid derivatives (U.S. Pat. No. 4,188,390, Feb. 12, 1980; Canadian Patent No. 1,088,059, Oct. 21, 1980; U.S. Pat. No. 4,287,341, Sep. 1, 1981; EP Patent 0,028,473 Al, Oct. 16, 1980; U.K. Patent GB 2,171,997A, Sep. 10, 1986). These patents explain the preparation of piperazine derivatives starts from normal esters. These esters are hydrolyzed using alkali to give acids, which are converted to acid chloride using SOCl.sub.2 (thionyl chloride) or chemical equivalents of it. These acid chlorides react with piperazine in the presence of mineral acids, which involves tedious working up procedures, pH adjustment, and extractions in order to obtain acceptable yields (U.S. Pat. No. 4,287,371, Sep. 1, 1981; Canadian Patent No. 1,088,059, Oct. 21, 1980; U.S. Pat. No. 4,188,390, Feb. 12, 1980; EP patent No. 0,028,473 Al, Oct. 16, 1980; J. Med. Chem. 1977, 20, 146-149; J. Med. Chem. 1987, 30, 49-57). These reactions involve corrosive reagents such as Thionyl chloride or oxalyl chloride and one or more equivalents of concentrated mineral acids (Hydrochloric acid, Hydrobromic acid, etc.) The mineral acids are used to protect one of the two nitrogens of piperazine to avoid diacylated product (B, in Scheme 3). In Canadian Letters Patent No. 1,057,754, in order to prepare the N-(Tetrahydro-2-furoyl) piperazine, the patentee hydrogenates the N-(2-furoyl) piperazine (used to produce prazosin whose process of manufacture is taught in the prior art).
Other methods, not quite commonly used, employ succinimido and pthalimido esters as activating groups (U.S. Pat. No. 4,188,390, Feb. 12, 1980). These procedures are also not industrially viable as they involve expensive reagents and a number of steps ##STR16## Scheme 3). For example, Succinimido ester is prepared conventionally by reacting the free acid with N-Hydroxy succinimide in presence of a dehydrating agent dicyclohexylcarbodiimide, which is highly toxic, corrosive and expensive (Review; Synthesis, 1981, 333 and references cited therein). This is the same with mixed anhydrides ##STR17## where R may be pivaloyl or isobutyl, Scheme 3).
It is therefore an object of this invention to provide a simple, new and efficient process for the synthesis of mono-N-Acyl piperazine derivatives which are useful and important intermediates used to manufacture quinazolines of general Formula 1 (eg. Doxazosin, Terazosin, Prazosin, Tiodazosin, etc.).
It is a further object of the invention to provide an improved, efficient and higher yielding process than those taught in the prior art.
It is still a further object of this invention to provide novel methods of preparing mono-N-Acyl piperazines including intermediates for Doxazosin, Terazosin, Prazosin and other antihypertensive medicines having an N-Acyl piperazine unit embodied in them.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of invention and detailed description of embodiments thereof.